Parkinson's disease (PD) is the second most common neurodegenerative disease affecting > 1% of aging humans. PD manifests in progressive movement disorder, which (in 50%-80% cases) is closely followed by memory loss and complex mental function impairment. However, molecular mechanism(s) behind PD and PD-associated dementia (PD/D) are not fully understood, hampering the discovery of much needed therapies. Bcl11b is a transcription factor, which we recently found to be involved in vascular smooth muscle cell and arterial function (Parent R01). But Bcl11b is also expressed in neurons in distinct brain regions that control motor function, and is crucial for neuronal cell lineage commitment during hemotopoieis and embryonic development. However, because Bcl11b deletion is lethal within 48 hours from birth, nothing is presently known about its potential role in PD and PD/D. In this Supplemental proposal, in collaboration with Dr. Bolotina we will focus on our recent discovery that neuronal Bcl11b can be upregulated in specific brain regions of idiopathic PD patients and mouse model of progressive human PD, where it strongly associates with aggregation of ?Synuclein (?Syn), a culprit of PD and PD/D. We seek to test the hypothesis that PLA2g6L-deficiency triggers Bcl11b upregulation in specific neuronal populations thereby stimulating ?Synucleinopathy, and initiating/accelerating PD and PD-associated dementia. By using advanced animal model, innovative in vivo/ex vivo approaches and our complementary expertises, we will test this hypothesis with two specific aims: (1) to examine changes in neuronal Bcl11b expression and its association with ?Syn aggregation in different areas of the brain from aged idiopathic PD patients in comparison with control donors; (2) to determine whether upregulation of neuronal Bcl11b and pathological ?Syn aggregation are triggered by PLA2g6L/Ca2+ signaling and associated with progressive PD-associated dementia in a mouse model of PD (Thy1-?SynhWT/PLA2g6ex2Cre-KO). Expression and co-localization of Bcl11b, ?Syn and PLA2g6L and other PD-related markers (tyrosine hydroxylase) will be assessed in putamen, cortex, basal ganglia, striatum, hippocampus and substantia nigra areas of postmortem brains of deceased idPD patients and Thy1-?SynhWT/PLA2g6ex2Cre-KO mice compared to controls using advanced immunohistochemical, imaging, behavioral tests and analytical approaches. Definitive demonstration of PLA2g6L/Ca2+/Bcl11b axis in ?Synucleinopathy and progressive behavior dysfunction will unveil a novel pathway that can be targeted to therapeutically prevent progression of PD and associated dementia.